Photochemotherapy and photodynamic therapy (PDT) are two techniques used to detect and/or treat tissue abnormalities. These techniques are based on the discovery made over 90 years ago that unicellular organisms, i.e., certain rapidly growing cells (such as cells of the Lower Kingdom, now referred to as Protista), treated with certain chemicals will die when exposed to light. Thus, synthetic porphyrins have been shown in vitro to protect cells from infections caused by organisms such as parasites, e.g., tyromastigotes and sphaeromastigotes of Tyropanosoma cruzi, J. PARASITOL., 75(6) 1989, p. 970-976, and gram positive bacteria, mycoplasma and yeasts, Malik et al. J. PHOTOCHEMISTRY AND PHOTOBIOLOGY, B. BIOLOGY 5 281-293 (1990). P. acne is known to, in vitro, produce intracellular protoporphyrin in the presence of exogenous ALA. Kjeldstad, Conference on Photosensitization and Photochemotherapy of Cancer, Det Norske Videnskaps-Akademi, Mar. 16-17, 1993, Oslo, Norway.
PDT has been approved for the palliation of malignant dysphagia, treatment of early recurrent lung cancer, palliation of endobronchial destruction, treatment of wet AMD, and treatment of nonhypertrophic facial actinic keratoses. The patient is given a photoactivatable drug that has some degree of specificity for the tissue being treated. A tissue volume that includes the target tissue is then exposed to photoactivating light so as to destroy the target tissue while causing only mild and reversible damage to the other tissues in the same treatment volume. A more detailed description of the uses of PDT are described in Marcus et al., EXPERT OPINION ON EMERGING DRUGS, 7(2):321-34 (2002), which is hereby incorporated by reference in its entirety.
One class of photodynamic therapy agents currently being used are porphyrins and related photosensitizers. These agents are given systemically (by intravenous injection), although occasionally they are given either topically or by intralesional injection. They can be activated by visible (red) light. The localized exposure of porphyrin-containing tissues to such light ordinarily does not induce a chemical reaction between cell components and the porphyrin molecules. Instead, the porphyrins act as catalysts by trapping the energy of the photoactivating light and then passing it on to molecules of oxygen, which in turn are raised to an excited state that is capable of oxidizing adjacent molecules or structures. Cell death is not caused primarily by damage to the DNA, but by damage to essential membrane structures. The goal of photodynamic therapy is sometimes cure (mainly for carcinomas), but usually the goal is palliation through local control when none of the standard forms of therapy are considered likely to offer a significant degree of benefit to the patient.
Another class of agents, aside from porphyrins, relates to agents which can be administered either systemically or topically and which are not themselves photosensitizers, but which induce the synthesis of protoporphyrin IX (PpIX). One such agent is 5-Amino-4-oxopentanoic acid, also known as 5-aminolevulinic acid or δ-aminolevulinic acid (“ALA”), has been described for detecting and treating rapidly growing cells. In addition to the use ALA, prodrugs of 5-aminolevulinic acid, such as esters of 5-aminolevulinic acid could be administered to a patient to induce the synthesis of PpIX. For example, U.S. Pat. No. 6,710,066 by Kennedy et al., U.S. Pat. No. 5,079,262 by Kennedy et al., U.S. Pat. No. 5,211,938 by Kennedy et al., U.S. Pat. No. 5,234,940 by Kennedy et al., U.S. Pat. No. 5,422,093 by Kennedy et al., U.S. Pat. No. 5,955,490 by Kennedy et al, U.S. Pat. No. 6,750,212 by Peng et al., and U.S. Pat. No. 6,492,420 by Gierskcky et al., each of which is hereby incorporated by reference in its entirety, teach the use of ALA. ALA has also been reported for use in attenuating the growth and killing of plants and insects when applied directly to such organisms followed by exposure to light, based on work of Rebeiz et al. In vivo, ALA leads to increased production of protoporphyrin IX, which is a porphyrin that induces photosensitivity.
Synthetic porphyrins have also been used as photodynamic therapeutic agents in treating rapidly growing, e.g. rapidly dividing or rapidly metabolizing infectious cells, such as infectious pathogens, including protozoal parasites, such as Plasmodium falciparium (which causes malaria in humans), various other species of Plasmodia, Leishmania, and amoebae, pathogenic fungi, and microplasma, including the various parasitic forms, all such cells and organisms being referred to herein as Protista. The term Protista as used here and in the literature refers to the lowest orders of the animal and vegetable kingdoms, single celled or collections of single celled organisms including: the eukaryotes, including protozoa, fungi and algae, and the prokaryotes, which are bacteria and blue-green algae.
At present, the most commonly used porphyrins for photodynamic therapy are Hematoporphyrin IX (HpIX), Hematoporphyrin derivative (HpD), and various semi-purified preparations of HpD such as commercially available Photofrin® II, a semi-purified form of HpD. When porphyrins are used as photosensitizers, cell death results from damage to cell membranes. Consequently, malignant transformation is not a serious problem.
However, the use of photosensitizers in photodynamic therapy does suffer from a major problem. Photosensitizing concentrations persist in the skin for several weeks to several months following their administration. Consequently, severe accidental phototoxic skin reactions may occur unless the patient avoids exposure to sunlight (either direct, or filtered through window glass) until the concentration of the photosensitizer in the skin has been reduced to a harmless level. At present, the problem of photosensitivity following the administration of the photosensitizer is handled by advising the patient to avoid any form of exposure to sunlight (or to very bright artificial lights) for a period of at least two weeks post-injection, and to initiate subsequent exposure to sunlight very cautiously. Not all patients comply with these instructions, since it often is quite inconvenient to do so. In addition, the use of a sunscreen with a high blocking factor is recommended with warning that this will only reduce the hazard somewhat, not eliminate it completely. In a few cases, patients whose photosensitization persisted for more than a month post-treatment have been given large daily doses of beta-carotene over a period of several months in an attempt to prevent accidental phototoxic damage. Finally, attempts have been made to reduce phototoxicity by applying the photosensitizer topically to a limited area. However, the success at reducing phototoxicity has been limited, and there is a need for compositions and methods that may be used to reduce photosensitivity in patients undergoing photochemotherapy.